This MDRC renewal brings together talented new and experienced investigators, unique resources, and innovative techniques to develop medications for the treatment of Cocaine. heroin. and marijuana abuse. Existing medications for treating heroin addiction have serious flaws, and no effective agents have been developed for the other two drugs of abuse. The current MDRC has as its major theme the development of effective medications for subgroups of the addict population and the search for better methods to identify them. The renewal expands this focus to the development and/or utilization of models for more efficient and productive testing of promising medications, and consists of two Cores and five Projects, among which there is considerable interaction. The Administrative/Clinical Core, in addition to centralized recruiting, coordination, support and provision of basic psychosocial therapy, will carry out placebo-controlled pilot studies on promising new medications, and supports inpatient and outpatient research facilities for pilots and projects. The Statistical, Education, and Training Core provides statistical support, from design to analysis, and extensive education (with our Fellowship program) to medical students, residents, and fellows. Project 1 uses the smoked heroin self-administration model developed in the current MDRC to evaluate the buprenorphine/naloxone combination tablet, depot naltrexone, and two NMDA receptor antagonists. Project 2 combines innovative imaging of the Dl and D2 receptors with our model of cocaine self-administration to investigate whether the DI/D2 ratio is associated with cocaine craving and seeking, and thus could be a marker for rational medication development. Project 3 using the targeted subgroup model and innovative design features, builds on a promising pilot of venlafaxine, expanding it to a major double-blind clinical trial in depressed cocaine abusers. Project 4 aims to develop and implement a screening model for potential new agents for heroin detoxification. Using a three-arm screening model, an alphaadrenergic agonist, a calcium channel blocker, two NMDA antagonists and two partial opioid agonists will be compared to the alpha- adrenergic agonist clonidine. Project 5 proposes to develop a model for studying the effects of potential treatment medications with marijuana abusers, evaluating agents that may either ameliorate marijuana abstinence symptoms or reduce marijuana's acute effects. Overall, the Center has the potential to develop better medications and models for treating abuse of these three drugs, and, to meet this goal, has the unique ability to rapidly move back and forth between human laboratory and clinical studies.